Continuous Flow Synthesis of Urea-Containing Compound Libraries Based on the Piperidin-4-one Scaffold

Article abstract of DOI:10.1002/ejoc.201701539

The advantages of performing reactions in continuous flow vs. the classic batch processes render flow chemistry a suitable technique for library synthesis. Inspired by our recent work to create fluorine-containing nitrogen heterocycles and by the potentia

Full text of DOI:10.1002/ejoc.201701539

A Journal of
Accepted Article
Title: Continuous Flow Synthesis of Urea-Containing Compound
Libraries Based on the Piperidin-4-one Scaffold
Authors: Alejandra Riesco-Dominguez, Daniel Blanco-Ania, and Floris
P. J. T. Rutjes
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701539
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10.1002/ejoc.201701539
European Journal of Organic Chemistry
FULL PAPER
Continuous Flow Synthesis of Urea-Containing Compound
Libraries Based on the Piperidin-4-one Scaffold
Alejandra Riesco-Domínguez,[a] Daniel Blanco-Ania,[a] and Floris P. J. T. Rutjes*[a]
Abstract: The advantages of performing reactions in continuous flow
versus the classic batch processes render flow chemistry a suitable
technique for library synthesis. Inspired by our recent work to create
fluorine-containing nitrogen heterocycles and by the potential of the
urea group in drug design, we herewith describe the combination of
both aspects in the continuous flow synthesis of two libraries of urea
derivatives based on the piperidin-4-one scaffold.
Recently, we reported an enantio- and diastereoselective
synthesis of piperidin-4-ones 2a–c from the enantiopure amino
ketone 1 (Scheme 1).6 Compounds 2a–c, containing three
different fluorine functionalities (F, CF3 and SF5) to enhance their
bioactivity and metabolic profile,7 were synthesized and further
derivatized into a novel library of spirocyclic compounds (3 and 4)
under classic batch processes via a diastereoselective Pictet–
Spengler cyclization.6
The inherent potential of this scaffold (2a–c) for derivatization
combined with the advantages of flow chemistry for library
synthesis8 (including excellent heat exchange and fast mixing for
better reaction control, automated small scale optimization and
rapid automated compound library preparation) encouraged us to
further develop a new class of urea derivatives in flow (5 and 6)
based on scaffolds 2a–c (Scheme 1).
Introduction
The urea group represents an important functionality in
pharmaceutical and agrochemical products.1 Urea-containing
molecules possess an immense potential in drug design as a
result of their capability for hydrogen-binding to biomolecular
targets.2 Moreover, ureas are widely used in drug design for the
modulation of several factors, such as selectivity, stability, toxicity
and pharmacokinetic profile of lead molecules.2 Examples of
active compounds containing a urea are depicted in Figure 1.
Trimefluor,3 a selective pre- and post-emergence herbicide for
use in cotton, and triflumuron,4 a broad spectrum insecticide
against chewing insects commercialized by Bayer CropScience,
are examples of bioactive molecules containing a urea group.
O
NH2.HCl
Ar
previous work
(batch)
this work
(flow)
R
1
HN
N
O
Ar
N
H
H
O
N
Ar1
N
H
Ar
R
Ar1
O
Another example of
vestipitant,5 a selective antagonist for the NK1 receptor.
a urea-containing pharmaceutical is
3
H
N
Ar1
5
N
H
Ar
HO
Ar
HN
2ac
H
N
N
CF3
Cl
O
Ar1 = 4-FC6H4 (2a)
Ar = 3,4-(MeO)2C6H3
R
H
N
H
N
Ar1
N
H
4
Ar
Ar1
O
HN
Me
N
4-CF3C6H4 (2b)
4-SF5C6H4 (2c)
N
6
CF3
O
OCF3
Me
O
Me
vestipitant
triflumuron
Cl
OCF3
Figure 1. Biologically active compounds containing a urea group.
Scheme 1. Previously reported work (batch) and this work (flow) based on
scaffolds 2a–c.
Me
H
N
N
Me
F
trimefluor
O
Results and Discussion
We started our investigations by testing the reactivity of our
amines (2b and 2c) with alkyl isocyanates (ethyl [7A] or isopropyl
isocyanate [7B], 1.5 equiv) varying solvent, temperature and
reaction time (see Table 1 for summarized results and Supporting
Information [SI] for the entire optimization process). All reactions
were carried out in a borosilicate glass reactor (channel width 600
µm, channel depth 500 µm and effective reactor volume 100 µL).9
The microreactor was placed into a microreactor holder, which
automatically aligns with the fluidic connections and makes
contact with the temperature controlled metal plate in the
micorreactor holder. Then, the inlet modules were connected
through the microreactor holder with the inlet ports of the
[a]
A. Riesco-Domínguez, Dr. D. Blanco-Ania, Prof. dr. F. P. J. T.
Rutjes
Institute for Molecules and Materials, Radboud University
Heyendaalseweg 135, 6525 AJ Nijmegen, the Netherlands
floris.rutjes@.ru.nl
http://www.ru.nl/syntheticorganicchemistry/
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10.1002/ejoc.201701539
European Journal of Organic Chemistry
FULL PAPER
microreactor and the outlet tubing was also placed at the outlet
port. The tubing was connected to the syringes, which were
connected to the pumps. The two solutions, one containing the
piperidin-4-ones (2b or 2c) and the other one with the isocyanates
7 were pumped and brought together inside of the microreactior
(Table 1). Initially, we used solvents such as MeCN or 1,2-
dichloroethane in a temperature range of 50–80 °C and reaction
times of 10–15 minutes (entries 1–4). Low conversions to ureas
5bA and 5bB were obtained in all these cases and only a slightly
higher conversion to 5bA (ratio 5bA/2b 1:0.7) was achieved when
we used MeCN at 50 °C (entry 1). The use of EtOH at 80 °C and
a reaction time of 10 minutes provided a ratio of 1:1.2 for 5bB/2b
(entry 5). An increase of the reaction time to 15 minutes (entry 6)
gave higher conversion into product 5bB (1:0.15). By increasing
the amount of isocyanate (2.0 and 2.5 equiv, entries 7 and 8,
respectively), nearly full conversion to 5bB and full conversion to
5cA were obtained. However, carbamate 8 was also formed in
the reaction mixture when EtOH was used as solvent, as a result
of the nucleophilic attack of EtOH to the isocyanate. Therefore,
we explored the use of bulkier alcohols as solvent (iPrOH and
tBuOH) to avoid the formation of 8. Thus, the reaction of piperidin-
4-one 2c with ethyl isocyanate (2.5 equiv) in the presence of
propan-2-ol gave full conversion to urea 5cA and less formation
of the carbamate 8 (entry 9) whereas the formation of 8 was
completely suppressed when tert-butyl alcohol was used (entry
10).10 With this result in hands, we tried to decrease the
temperature of the reaction and the amount of isocyanate used.
We confirmed that when using 2.0 equiv of ethyl isocyanate and
temperatures between 25–35 °C full conversion was not reached
(entries 11 and 12). Finally, we found that the use of 2.0 equiv of
ethyl isocyanate at 50 °C in tBuOH were the suitable conditions to
obtain full conversion to compound 5cA (entry 13). Once the
conditions for the synthesis of aliphatic ureas were optimized, we
attempted the synthesis of the aryl derivatives. Therefore, we first
explored the reaction of 2b with 2,4-difluorophenyl isocyanate (7E,
1.5 equiv) at 80 °C in EtOH and a reaction time of 20 minutes; the
reaction, however, did not show any conversion to product 5bE
and it resulted in a mixture of 2b and carbamate 8 (ratio 2b/8d
1:0.50; entry 14).
Table 1. Optimization process for the synthesis of alkyl and aryl ureas 5b and 5c.
O
O
P1
Ar1
N
Ar
H
M
O
Ar1 = 4-CF3C6H4 (2b)
Ar1 = 4-SF5C6H4 (2c)
2b 2c
,
R1
Ar1
R
R
N
Ar
O
N
O
H
P2
R
N
H
O
Ar = 3,4-(MeO)2C6H3
N
7
5b 5c
,
8
conditions
Table 1
time
(min)
Flow rate
Entry
Substrate
7 (equiv)
Solvent
t (°C)
Product
8
R
R1
Ratio 5/2/8[a]
(µL/min)
10.00
10.00
6.67
1
2
2b
2b
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
2c
7A(1.5)
7A(1.5)
7A(1.5)
7B (1.5)
7B (1.5)
7B (1.5)
7B (2.0)
7A(2.5)
7A(2.5)
7A(2.5)
7A(2.0)
7A(2.0)
7A(2.0)
MeCN
MeCN
MeCN
1,2-DCE
EtOH
50
80
80
80
80
80
80
80
80
80
25
35
50
10
10
15
15
10
15
17
17
17
17
17
17
17
5bA
5bA
5bA
5bB
5bB
5bB
5bB
5cA
5cA
5cA
5cA
5cA
5cA
–
–
CH3CH2
CH3CH2
CH3CH2
(CH3)2CH
(CH3)2CH
(CH3)2CH
(CH3)2CH
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
–
–
–
–
1:0.7:0[b]
1:10:0
3
–
1:5.0:0
4
–
1:6.0:0
6.67
5
8a
8a
8a
8b
8c
–
CH3CH2
CH3CH2
CH3CH2
CH3CH2
1:1.2:0.14
1:0.15:0.31
1:0.08:0.31
1:0:0.92
1:0:0.6
10.0
6
EtOH
6.67
7
EtOH
5.88
8
EtOH
5.88
9
iPrOH
tBuOH
tBuOH
tBuOH
tBuOH
(CH3)2CH
5.88
10
11
12
13
–
–
–
–
1:0:010
5.88
–
1:0.12:011
1:0.10:011
1:0:011
5.88
–
5.88
–
5.88
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10.1002/ejoc.201701539
European Journal of Organic Chemistry
FULL PAPER
14
15
2b
2b
7E (1.5)
7E (1.3)
EtOH
80
80
20
17
5bE
5bE
8d
2,4-F2C6H3
2,4-F2C6H3
CH3CH2
–
0:1:0.50
5.00
5.88
1,2-DCE
–
1:0:0
[a] Calculated by 1H NMR of the fraction of the collected product. [b] Analyzed by 1H NMR of the fraction of stabilization time.
By changing the solvent to 1,2-dichloroethane, and using 1.3
equiv of isocyanate 7E, full conversion to compound 5bE was
obtained (entry 15).
With the final conditions in hands, five isocyanates 7A–E (alkyl
O
O
N
N
7A
7B
and aryl isocyanates with different substituents on the phenyl ring,
Figure 2) were selected for the generation of a 15-compound
Cl
F
F
library (Table 2). For all experiments, three fractions (stabilization
O
O
O
N
time, collected product and residual) were collected in separated
vials and final products were analyzed directly by H NMR from
N
N
1
7C
7D
7E
the fraction of collected product. This fraction always started after
running three cycles of the stabilization time (see [SI] for
experimental details).12
Figure 2. Isocyanates used for the generation of the library.
The reaction of piperidin-4-ones 2a–c with alkyl isocyanates 7A
and 7B gave full conversions to products 5aA–cB in very good to
excellent yields (83–92%).
Table 2. Library of ureas 5aA–cE based on the piperidin-4-one scaffold.
O
N
O
N
O
N
O
N
O
N
Ar
NH
Ar
NH
Ar
NH
Ar
NH
Ar
NH
O
F
F
F3C
F5S
2a
O
O
F
F3C
F5S
F
F3C
F5S
O
O
F
F3C
F5S
F
F3C
F5S
Cl
F
5aA[a]
99%,[c] 83%[d]
5aB[a]
99%,[c] 84%[d]
5aC[b]
5aD[b]
5aE[b]
99%,[c] 89%[d]
99%,[c] 73%[d]
99%,[c] 97%[d]
O
O
O
O
O
N
Ar
NH
N
N
Ar
NH
Ar
NH
N
Ar
NH
N
Ar
NH
O
F
O
O
2b
O
O
Cl
F
5bA[a]
99%,[c] 85%[d]
5bB[a]
99%,[c] 89%[d]
5bC[b]
5bD[b]
5bE[b]
99%,[c] 88%[d]
99%,[c] 77%[d]
99%,[c] 55%[d]
O
O
O
O
O
N
Ar
NH
N
Ar
NH
N
Ar
NH
N
Ar
NH
N
Ar
NH
O
F
O
O
2c
O
O
Cl
F
5cA[a]
99%,[c] 92%[d]
5cB[a]
99%,[c] 92%[d]
5cC[b]
99%,[c] 99%[d]
5cD[b]
99%,[c] 99%[d]
5cE[b]
99%,[c] 87%[d]
[a] Reaction carried out in tBuOH at 50 °C in 17 minutes using 2.0 equiv of isocyanate. [b] Reaction carried out in 1,2-dicloroethane at 80 °C in 17 minutes using
1.3 equiv of isocyanate. [c] Conversion calculated by 1H NMR of the fraction of collected product. [d] Isolated yield of the fraction of collected product.
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10.1002/ejoc.201701539
European Journal of Organic Chemistry
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O
N
We also obtained full conversions to ureas 5aC–cE when aryl
isocyanates (7C–E) were used. Very good to excellent yields
were obtained for compounds 5aC, 5aE, 5bC and 5cC–cE. Good
yields were obtained for compounds 5aD and 5bD whereas
compound 5bE was obtained with a moderate yield. The excess
of isocyanates was removed in vacuo as much as possible so that
only small amounts of the least volatile isocyanates remained in
the reaction mixtures. The crude mixtures of compounds 5bA and
5bB showed the presence of a minor product in a 1:0.1 ratio
according to their 1H NMR spectra. We attributed these mixtures
to be either rotamers of the urea group or a possible mixture of
atropisomers, with the carbamoyl group (almost) perpendicular to
the piperidine ring (Figure 3), both caused by the congested 2,6-
diphenylpiperidine-1-carboxamide framework. For ureas 5bC and
5bD, the ratio of the isomers could not be measured accurately
whereas for the rest of ureas only one of both isomers was
observed.
O
X
O
N
OCD3
R
Ar1
R
Ar
R
N
Ar1
N
X
Ar
D
O
O
D3CO
N
H
1
2a 2c
,
7
9
10
X =
H
, D
5aC
R = C6H5
i
R = Pr 5cB
Scheme 2. Methanolysis of ureas 5aC and 5cB.
We also studied the decomposition of the aliphatic urea 5cB,
which also showed the presence of carbamates 9 and 10
(detected by GC-MS) and the starting material 2c (protonated and
deuterated substrates).
Finally, a diastereoselective reduction of ketone 2c was carried
out in flow using LiBH4 as reducing reagent to provide full
conversion to a 10:1 mixture of piperidinols 11 and 12 (Scheme
3). The workup of this reaction was performed offline after the
reaction mixture was completely collected in the corresponding
vial. The reduction of ketone 2b was performed in batch using N-
Selectride14 to give alcohol 12.15
O
N
O
N
Ar1
Ar1
Ar
NH
Ar
HN
R
O
O
R
Ar1 = 4-CF3C6H4, R = Et 5bA
H
OH
O
LiBH4
N-Selectride
i
Ar1 = 4-CF3C6H4, R = Pr 5bB
Ar
HN
Ar1
O
N
O
N
Ar
HN
Ar1
H
Ar
HN
Ar1
OH
THF, 1.5 h
91%
THF, 3 min
76%
12
Ar1 = 4-CF3C6H4
2b or 2c
11
dr 11 12
Ar1
Ar1
Ar
Ar
/
10:1
Ar1 = 4-SF5C6H4
NH
R
O
NH
R
O
Scheme 3. Reduction of 2a and 2c with N-Selectride and LiBH4.
Figure 3. Rotamers and atropisomers of 5bA and 5bB.
Then, we decided to perform the urea synthesis using as starting
material amino alcohol 11 (Table 3). Initially, we performed the
reaction between 11 and isocyanate 7B using the conditions
previously developed for aliphatic isocyanates (tBuOH, 17 min
and 50 °C). We decreased the amount of 7B to 1.0 equiv, to firstly
test the reactivity of our hindered amine in the presence of the
nucleophilic alcohol. We confirmed by 1H NMR that only the
amine group reacted with the isocyanate and therefore the
corresponding carbamate was not observed. However, while
using 1.0 equiv of isocyanate, a ratio 11/6b 1:0.5 was obtained.
Thus, we increased the amount of isocyanate 7B to 1.5 equiv and
full conversion to urea 6b was achieved (84% yield). When we
applied these conditions using ethyl (7A) and benzyl (7F)
isocyanates, amino alcohol 11 was converted with full conversion
to ureas 6a and 6c16 in 85 and 99% yield, respectively. Finally,
two additional examples with aryl isocyanates (7C and 7D) were
synthesized. In this case, the use of 1.1 equiv of isocyanate in
1,2-DCE at 80 °C was sufficient to reach full conversion to ureas
6d and 6e. For compounds 6a–e, a 6:1 ratio of conformers was
obtained.
Optimization of these reactions to obtain full conversion was
crucial because no further column chromatography was required.
Purifying these poorly soluble ureas generally requires polar
solvents such as MeOH, but in case of sterically congested ureas
methanolysis13 may take place in the purification process. In this
case, methanolysis occurred because the nitrogen in the
piperidine ring might not be fully conjugated anymore with the
carbonyl and therefore MeOH can form a hydrogen bond with the
nitrogen. To analyze the reactivity of these ureas in MeOH, we
1
dissolved urea 5aC in CD3OD and monitored the mixture by H
NMR (Scheme 2). We observed that compound 5aC was still
present after 1–4 h, but after 19 h at room temperature compound
5aC transformed into piperidin-4-one 2a (protonated and
deuterated substrates), phenyl isocyanate 7C and carbamates 9
and 10 (relative abundance 9/10 30:70). 1H NMR showed a
mixture of compounds which was confirmed by GC-MS (Scheme
2).
Table 3. Library of ureas 6a–e based on amino alcohol 11.
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10.1002/ejoc.201701539
European Journal of Organic Chemistry
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OH
N
4
5
6
7
8
H5
H6
H7
H8
H9
2.70/2.00
5.65
2.37/2.20–2.10
5.12
O
OH
R
N
7
Ar1 = 4-SF5C6H4
Ar1
R
Ar
Method A[a]
or B[b]
Ar1
N
H
Ar
3.80–3.70
0.88
3.58–3.49
0.72
Ar = 3,4-(MeO)2C6H3
N
O
H
11
6
HO
Ar
HO
Ar
HO
Ar
H
0.74
0.60
H
H
N
N
N
N
N
N
Ph
Ar1
O
Ar1
O
Ar1
O
6a[a]
99%,[c] 85%[d]
6b[a]
99%,[c] 84%[d]
6c[a]
99%,[c] 99%[d]
Conclusions
HO
Ar
H
HO
Ar
O
In summary, we have synthesized a small library of ureas in
continuous flow. The reactions utilized for their syntheses were
achieved in a reaction time of 17 min without further need of
purification rendering drug-like molecules. Moreover, we have
also reduced diastereoselectively the ketone group in flow in 3
min reaction time. Additional urea formation of amino alcohol 11
was also performed to create five different urea derivatives. NMR
studies confirmed the formation of conformers caused by the
hindered rotation around one of the single N–CO bonds of the
urea. The elucidation of these species to be identified as either
rotamers or atropisomers could not be clarified. This methodology
could be applied to a wide range of substrates as a tool to prepare
libraries of potentially bioactive molecules.
Cl
H
N
N
N
N
Ar1
O
Ar1
6d[b]
99%,[c] 99%[d]
6e[b]
99%,[c] 83%[d]
t
[a] Reaction carried out in BuOH at 50 °C in 17 minutes using 1.5 equiv of
isocyanate. [b] Reaction carried out in 1,2-dicloroethane at 80 °C in 17 minutes
using 1.1 equiv of isocyanate. [c] Conversion calculated by 1H NMR of the
fraction of collected product. [d] Isolated yield of the fraction of collected product.
As previously mentioned, the presence of the conformers
(rotamers or atropisomers) was caused by the hindered rotation
around one of the single N–CO bonds of the urea.17 NOESY
experiments of compound 13a (the major product of reaction
between alcohol 12 and isocyanate 7B) showed correlations
between the NH of the urea with both benzylic protons (Table 4),
indicating therefore the existence of atropisomerism (in case of
rotamers, each rotamer would show only one correlation with one
benzylic proton).18 The assignment of the characteristic protons is
depicted in Table 4. Chemical shifts of compounds 13a and 13b19
present a considerable difference, not only for the benzylic
protons H2 and H6 (entries 1 and 5), but also for protons H4 and
H7 (entries 3 and 6). We were also able to confirm that the major
product of the stereoisomers was compound 13a, which showed
a correlation between the NH proton of the urea and both benzylic
protons, H2 and H6. The clarification of these two products was
done by NOESY studies.
Experimental Section
General information: Reagents were obtained from commercial suppliers
and were used without purification. Standard syringe techniques were
applied for the transfer of dry solvents and air- or moisture-sensitive
reagents. Reactions were followed by 1H NMR, and RF values were
obtained, using thin layer chromatography (TLC) on silica gel-coated
plates (Merck 60 F254) with the indicated solvent mixture. Detection was
performed with UV light, and/or by charring at ca. 150 °C after dipping into
a solution of KMnO4. Infrared spectra were recorded on an IR-ATR Bruker
TENSOR 27 spectrometer. High-resolution or accurate mass
measurement (ΔM < 3mmu or 5ppm) were recorded on a JEOL AccuTOF-
CS JMS-T100CS for Electrospray (spectra recorded in infusion in MeOH
containing 50nM PPG-475 as internal mass-drift compensation standard)
or JEOL AccuTOF-GCv JMS-T100GCv (GC/Electron Ionization MS,
column bleeding at high temperature used as internal mass drift
compensation standard) for methanolysis experiments. NMR spectra were
recorded at 298 K on a Varian Inova 400 (400 MHz), Bruker Avance III 400
MHz or Bruker Avance III 500 MHz spectrometer in the solvent indicated.
Chemical shifts are given in parts per million (ppm) with respect to
tetramethylsilane (0.00 ppm) as internal standard for 1H NMR; and CDCl3
(77.16 ppm) as internal standard for 13C NMR. Coupling constants are
reported as J values in hertz (Hz). 1H NMR data are reported as follows:
chemical shift (ppm), multiplicity (s = singlet, d = doublet, dd = doublet of
doublets, dt = doublet of triplets, dq = doublet of quartets, ddd = doublet of
doublet of doublets, quint = quintet, t = triplet, td = triplet of doublets, m =
multiplet), coupling constants (Hz), and integration. Compounds were fully
characterized by 1H, 13C, COSY, HSQC, HMBC and NOESY. Reactions
were carried out using the FlowStart Evo equipment and microreactors
purchased by FutureChemistry (futurechemistry.com accessed Sep 11,
2017). At very low flow rates, stabilization and pressure of the equipment
may take long; therefore, a stabilization time is calculated and run before
the collecting product fraction. The stabilization time is calculated following
equation 1:
Table 4. Chemical shifts (ppm) of atropisomers 13a and 13b in CDCl3.
H4
H3
H4
H3
HO
HO
H5
H5
H5
H5
O
H3
H3
N
7B
Ar1
Ar1
12
N
Ar
N
Ar
H6 H2
NH
H6 H2
NH
H7
Me
NOE
O
O
H7
Me
Me
Me
13a
13b
Entry
1H
H2
H3
H4
ppm (13a)
4.89
ppm (13b)
1
2
3
4.36
2.11/1.84
4.43
2.20–2.10/2.00–1.89
4.16
⁄
ꢀꢁꢂꢃꢄꢅꢄꢆꢂꢁꢄꢇꢈ ꢉꢄꢊꢋ ꢌ 3 ꢍ ꢎꢋꢂꢏꢁꢇꢐ ꢑꢇꢅꢒꢊꢋ ꢉꢇꢁꢂꢅ ꢓꢅꢇꢔ ꢎꢂꢁꢋ
(Eq1)
For all reactions, products were analyzed from the collected fraction and
therefore calculations and yields and based on this fraction.
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10.1002/ejoc.201701539
European Journal of Organic Chemistry
FULL PAPER
General Procedure for the Synthesis of Alkyl Ureas 5aA, 5aB, 5bA,
5bB, 5cA and 5cB
Solution A: piperidin-4-one (2a–c, 1.0 equiv) dissolved in BuOH (99.8–
2969, 1721, 1639, 1605, 1510, 1263, 1228, 1026, 854. HRMS [ESI (m/z)]
calcd for (C23H27FN2O4 + Na)+ = 437.18471, found 437.18465 (|Δ| = 1.4
ppm). RF: 0.41 (heptane/AcOEt, 1:2). Yield: 84%.
t
100.2 mM). Solution B: alkyl isocyanate (7A or 7B, 2.0 equiv) dissolved in
tBuOH (0.1 M). Solution A (1.96 µL/min) was combined with B (3.92
µL/min) inside the glass microreactor (internal volume: 100 µL). The
reaction was performed at 50 °C for 17 min.
(2S,6R)-2-(3,4-Dimethoxyphenyl)-N-isopropyl-4-oxo-6-[4-
(trifluoromethyl)phenyl]piperidine-1-carboxamide 5bB
According to the general procedure, the reaction of piperidin-4-one 2b
t
(4.10 mg, 0.01 mmol) in BuOH (100.2 mM) with 7B afforded 5bB (4.48
(2S,6R)-2-(3,4-Dimethoxyphenyl)-N-ethyl-6-(4-fluorophenyl)-4-
oxopiperidine-1-carboxamide 5aA
mg, 9.65 µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.66–7.60 (m, 2 H),
7.57–7.51 (m, 2 H), 6.80 (d, J = 8.2 Hz, 1 H), 6.75 (ddd, J = 8.2, 2.2, 0.5
Hz, 1 H), 6.55 (d, J = 2.1 Hz, 1 H), 6.16 (t, J = 5.2 Hz, 1 H), 5.11 (dd, J =
10.2, 4.9 Hz, 1 H), 4.33 (d, J = 7.2 Hz, 1 H), 3.88–3.82 (m, 1 H), 3.86 (s, 3
H), 3.68 (s, 3 H), 3.18 (dd, J = 18.4, 4.7 Hz, 1 H), 2.87 (dd, J = 18.4, 5.7
Hz, 1 H), 2.74 (dd, J = 17.5, 10.2 Hz, 1 H), 2.61 (dd, J = 17.5, 4.9 Hz, 1 H),
0.97 (d, J = 6.5 Hz, 3 H), 0.82 (d, J = 6.5 Hz, 3 H). 13C NMR [101 MHz, δ
(ppm), CDCl3]: 207.2, 158.3, 150.3, 149.2, 147.5, 134.8, 129.9 (indirect
observation), 127.3, 126.1 (q, J = 3.6 Hz), 122.5 (indirect observation),
117.9, 111.5, 108.7, 56.5, 56.1, 56.0, 52.3, 46.5, 43.3, 42.9, 23.3, 23.0.
According to the general procedure, the reaction of piperidin-4-one 2a
t
(3.63 mg, 0.011 mmol) in BuOH (99.8 mM) with 7A afforded urea 5aA
(3.67 mg, 9.16 µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.39–7.31 (m,
2 H), 7.08–7.01 (m, 2 H), 6.80 (d, J = 8.2 Hz, 1 H), 6.75 (dd, J = 8.2, 2.1
Hz, 1 H), 6.64 (d, J = 2.1 Hz, 1 H), 6.00 (t, J = 5.4 Hz, 1 H), 5.22 (dd, J =
9.7, 4.9 Hz, 1 H), 4.40 (t, J = 5.2 Hz, 1 H), 3.86 (s, 3 H), 3.73 (s, 3 H), 3.18–
3.07 (m, 3 H), 2.88–2.73 (m, 2 H), 2.60 (dd, J = 17.6, 4.9 Hz, 1 H), 0.88 (t,
J = 7.2 Hz, 3 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 207.8, 162.1 (d, J
= 247.5 Hz), 159.1, 150.1, 149.0, 139.0 (d, J = 3.1 Hz), 134.9, 128.4 (d, J
= 8.0 Hz), 117.9, 116.0 (d, J = 21.5 Hz), 111.4, 108.9, 56.1, 56.0, 52.4,
FTIR [ꢕ̅
(cm−1)]: 3417, 2968, 1722, 1642, 1516, 1326, 1262, 1238, 1123,
767. HRMS [ESI (m/z)] calcd for (C24H27F3N2O4 + Na)+ = 487.18151, found
487.18134 (|Δ| = 1.5 ppm). RF: 0.41 (heptane/AcOEt, 1:2). Yield: 89%.
46.1, 43.6, 36.2, 15.2. FTIR [ꢕ
1264, 1228, 1025. HRMS [ESI (m/z)] calcd for (C22H25FN2O4 + Na)+
̅
(cm−1)]: 3420, 2967, 1722, 1639, 1511,
=
423.16906, found 423.16916 (|Δ| = 1.0 ppm). RF: 0.27 (heptane/AcOEt,
1:2). Yield: 83%.
(2S,6R)-2-(3,4-Dimethoxyphenyl)-N-isopropyl-4-oxo-6-[4-
(pentafluoro-λ6-sulfanyl)phenyl]piperidine-1-carboxamide 5cB
According to the general procedure, the reaction of piperidin-4-one 2c
(4.76 mg, 0.01 mmol) in tBuOH (99.9 mM) with 7B afforded 5cB (5.22 mg,
9.99 µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.78–7.73 (m, 2 H), 7.56–
7.50 (m, 2 H), 6.80 (d, J = 8.2 Hz, 1 H), 6.75 (dd, J = 8.2, 2.1 Hz, 1 H), 6.49
(d, J = 2.1 Hz, 1 H), 6.22 (t, J = 5.1 Hz, 1 H), 5.04 (dd, J = 10.4, 5.0 Hz, 1
H), 4.36 (d, J = 7.2 Hz, 1 H), 3.86 (s, 3 H), 3.66 (s, 3 H), 3.18 (dd, J = 18.4,
4.3 Hz, 1 H), 2.89 (dd, J = 18.4, 5.7 Hz, 1 H), 2.71 (dd, J = 17.5, 10.4 Hz,
1 H), 2.60 (dd, J = 17.5, 5.0 Hz, 1 H), 0.99 (d, J = 6.5 Hz, 3 H), 0.82 (d, J
= 6.5 Hz, 3 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 206.9, 158.3, 152.9
(indirect observation), 150.4, 149.3, 147.4, 134.6, 127.3, 126.8–126.6 (m),
117.9, 111.5, 108.5, 56.8, 56.2, 55.9, 51.8, 46.8, 43.3, 42.6, 23.3, 23.0.
(2S,6R)-2-(3,4-Dimethoxyphenyl)-N-ethyl-4-oxo-6-[4-
(trifluoromethyl)phenyl]piperidine-1-carboxamide 5bA
According to the general procedure, the reaction of piperidin-4-one 2b
t
(4.68 mg, 0.012 mmol) in BuOH (100.2 mM) with 7A afforded urea 5bA
(4.74 mg, 0.011 mmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.66–7.60 (m,
2 H), 7.56–7.51 (m, 2 H), 6.80 (d, J = 8.2 Hz, 1 H), 6.75 (ddd, J = 8.2, 2.1,
0.5 Hz, 1 H), 6.54 (d, J = 2.1 Hz, 1 H), 6.20 (t, J = 5.2 Hz, 1 H), 5.12 (dd, J
= 10.2, 4.9 Hz, 1 H), 4.44 (t, J = 5.2 Hz, 1 H), 3.86 (s, 3 H), 3.67 (s, 3 H),
3.23–3.11 (m, 3 H), 2.86 (dd, J = 18.4, 5.6 Hz, 1 H), 2.74 (dd, J = 17.5,
10.2 Hz, 1 H), 2.61 (dd, J = 17.5, 4.9 Hz, 1 H), 0.90 (t, J = 7.2 Hz, 3 H). 13
C
NMR [101 MHz, δ (ppm), CDCl3]: 207.2, 159.1, 150.3, 149.2, 147.4, 134.6,
129.9 (indirect observation), 127.3, 126.1 (q, J = 3.6 Hz), 124.0 (q, J =
272.2 Hz), 117.9, 111.5, 108.7, 56.6, 56.1, 56.0, 52.3, 46.6, 42.9, 36.2,
15.2. FTIR [ꢕ̅
(cm−1)]: 3422, 2970, 1722, 1635, 1517, 1327, 1264, 1238,
1123, 725. HRMS [ESI (m/z)] calcd for (C23H25F3N2O4 + Na)+ = 473.16586,
found 473.16547 (|Δ| = 2.0 ppm). RF: 0.28 (heptane/AcOEt, 1:2). Yield:
85%.
FTIR [ꢕ
̅
(cm−1)]: 3421, 2970, 1723, 1642, 1517, 1263, 1238, 842. HRMS
[ESI (m/z)] calcd for (C23H27F5N2O4S
+
Na)+
=
545.15039, found
545.15003 (|Δ| = 1.7 ppm). RF: 0.45 (heptane/AcOEt, 1:2). Yield: 92%.
Synthesis and Full Characterization of Aryl Ureas 5aC–aE, 5bC–bE
and 5cC–cE
Solution A: piperidin-4-one (2a–c, 1.0 equiv) dissolved in 1,2-DCE (78.5–
102.5 mM). Solution B: aryl isocyanate (7C, 7D or 7E, 1.3 equiv) dissolved
in 1,2-DCE (0.1 M). Solution A (2.56 µL/min) was combined with B (3.32
µL/min) inside the glass microreactor (internal volume: 100 µL). The
reaction was performed at 80 °C for 17 min.
(2S,6R)-2-(3,4-Dimethoxyphenyl)-N-ethyl-4-oxo-6-[4-(pentafluoro-λ6-
sulfanyl)phenyl]piperidine-1-carboxamide 5cA
According to the general procedure, the reaction of piperidin-4-one 2c
(2.21 mg, 5.05 µmol) in tBuOH (99.9 mM) with 7A afforded urea 5cA (2.37
mg, 4.66 µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.81–7.71 (m, 2 H),
7.55–7.49 (m, 2 H), 6.80 (d, J = 8.2 Hz, 1 H), 6.76 (dd, J = 8.2, 2.0 Hz, 1
H), 6.48 (d, J = 2.0 Hz, 1 H), 6.25 (t, J = 5.1 Hz, 1 H), 5.07 (dd, J = 10.3,
5.0 Hz, 1 H), 4.47 (t, J = 5.2 Hz, 1 H), 3.86 (s, 3 H), 3.66 (s, 3 H), 3.24–
3.09 (m, 3 H), 2.88 (dd, J = 18.5, 5.8 Hz, 1 H), 2.72 (dd, J = 17.6, 10.4 Hz,
1 H), 2.61 (dd, J = 17.6, 5.0 Hz, 1 H), 0.91 (t, J = 7.2 Hz, 3 H). 13C NMR
[101 MHz, δ (ppm), CDCl3]: 206.9, 159.0, 153.1 (indirect observation),
150.4, 149.2, 147.2 (indirect observation), 134.4, 127.3, 126.7 (indirect
observation), 117.9, 111.5, 108.5, 56.8, 56.1, 55.9, 51.9, 46.8, 42.7, 36.3,
(2S,6R)-2-(3,4-Dimethoxyphenyl)-6-(4-fluorophenyl)-4-oxo-N-
phenylpiperidine-1-carboxamide 5aC
According to the general procedure, the reaction of piperidin-4-one 2a
(2.59 mg, 7.86 µmol) in 1,2-DCE (88.9 mM) with 7C afforded 5aC (3.15
mg, 7.02 µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.45–7.38 (m, 2 H),
7.25–7.18 (m, 2 H), 7.12–7.05 (m, 2 H), 7.05–6.98 (m, 3 H), 6.89–6.83 (m,
2 H), 6.65 (d, J = 1.7 Hz, 1 H), 6.60 (s, 1 H), 6.19 (t, J = 5.3 Hz, 1 H), 5.35
(dd, J = 10.1, 4.9 Hz, 1 H), 3.89 (s, 3 H), 3.72 (s, 3 H), 3.21 (dd, J = 18.4,
4.9 Hz, 1 H), 2.95–2.85 (m, 2 H), 2.67 (dd, J = 17.6, 4.9 Hz, 1 H). 13C NMR
[101 MHz, δ (ppm), CDCl3]: 207.2, 162.3 (d, J = 247.8 Hz), 156.6, 150.6,
149.5, 138.6, 138.5 (d, J = 3.4 Hz), 134.3, 129.1, 128.6 (d, J = 8.0 Hz),
123.7, 120.0, 118.1, 116.3 (d, J = 21.4 Hz), 111.7, 108.9, 56.6, 56.2, 56.1,
15.2. FTIR [ꢕ̅
(cm−1)]: 3431, 2925, 1723, 1643, 1518, 1264, 1239, 844.
HRMS [ESI (m/z)] calcd for (C22H25F5N2O4S + Na)+ = 531.13474, found
531.13535 (|Δ| = 0.1 ppm). RF: 0.26 (heptane/AcOEt, 1:2). Yield: 92%.
52.3, 46.3, 43.4. FTIR [ꢕ
1235, 1026, 754. HRMS [ESI (m/z)] calcd for (C26H25FN2O4 + Na)+
̅
(cm−1)]: 3388, 2924, 1722, 1662, 1510, 1265,
=
(2S,6R)-2-(3,4-Dimethoxyphenyl)-6-(4-fluorophenyl)-N-isopropyl-4-
oxopiperidine-1-carboxamide 5aB
471.16906, found 471.16910 (|Δ| = 1.1 ppm). RF: 0.24 (heptane/AcOEt,
2:1). Yield: 89%.
According to the general procedure, the reaction of piperidin-4-one 2a
(3.50 mg, 0.01 mmol) in tBuOH (99.8 mM) with 7B afforded 5aB (3.72 mg,
8.98 µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.40–7.31 (m, 2 H), 7.09–
7.00 (m, 2 H), 6.80 (d, J = 8.2 Hz, 1 H), 6.75 (ddd, J = 8.2, 2.1, 0.6 Hz, 1
H), 6.67 (d, J = 2.1 Hz, 1 H), 5.95 (t, J = 5.5 Hz, 1 H), 5.23 (dd, J = 9.6, 4.9
Hz, 1 H), 4.29 (d, J = 7.2 Hz, 1 H), 3.88–3.80 (m, 1 H), 3.86 (s, 3 H), 3.74
(s, 3 H), 3.10 (dd, J = 18.2, 5.5 Hz, 1 H), 2.83 (dd, J = 17.7, 9.5 Hz, 1 H),
2.79 (dd, J = 18.2, 5.9 Hz, 1 H), 2.61 (dd, J = 17.6, 4.9 Hz, 1 H), 0.94 (d, J
= 6.5 Hz, 3 H), 0.83 (d, J = 6.5 Hz, 3 H). 13C NMR [101 MHz, δ (ppm),
CDCl3]: 207.8, 162.2 (d, J = 247.3 Hz), 158.4, 150.2, 149.0, 139.1 (d, J =
3.2 Hz), 135.1, 128.5 (d, J = 8.0 Hz), 117.9, 116.0 (d, J = 21.4 Hz), 111.4,
(2S,6R)-2-(3,4-Dimethoxyphenyl)-4-oxo-N-phenyl-6-[4-
(trifluoromethyl)phenyl]piperidine-1-carboxamide 5bC
According to the general procedure, the reaction of piperidin-4-one 2b (2.1
mg, 5.54 µmol) in 1,2-DCE (82.8 mM) with 7C afforded 5bC (2.43 mg, 4.87
µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.69–7.64 (m, 2 H), 7.62–7.57
(m, 2 H), 7.25–7.19 (m, 2 H), 7.06–6.99 (m, 3 H), 6.89–6.85 (m, 2 H), 6.64
(s, 1 H), 6.53–6.51 (m, 1 H), 6.41 (t, J = 5.0 Hz, 1 H), 5.22 (dd, J = 10.8,
4.8 Hz, 1 H), 3.89 (s, 3 H), 3.65 (s, 3 H), 3.29 (dd, J = 18.6, 4.1 Hz, 1 H),
2.98 (dd, J = 18.6, 5.8 Hz, 1 H), 2.80 (dd, J = 17.5, 10.8 Hz, 1 H), 2.66 (dd,
109.1, 56.1, 55.9, 52.5, 46.0, 43.7, 43.2, 23.3, 23.0. FTIR [ꢕ̅
(cm−1)]: 3420,
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10.1002/ejoc.201701539
European Journal of Organic Chemistry
FULL PAPER
J = 17.5, 4.8 Hz, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 206.6, 156.7,
150.7, 149.7, 146.7, 138.5, 133.9, 130.2 (indirect observation), 129.1,
127.4, 126.2 (q, J = 3.6 Hz), 125.9 (indirect observation), 123.9, 120.0,
9.7, 5.1 Hz, 1 H), 3.85 (s, 3 H), 3.68 (s, 3 H), 3.21 (dd, J = 18.6, 5.0 Hz, 1
H), 2.94 (dd, J = 18.6, 5.8 Hz, 1 H), 2.86 (dd, J = 17.6, 9.7 Hz, 1 H), 2.74
(dd, J = 17.6, 5.1 Hz, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 206.3,
156.4, 153.3 (indirect observation), 150.4, 149.5, 146.4, 135.6, 133.2,
129.1, 127.6, 127.4, 127.0–126.8 (m), 124.3, 123.2, 122.4, 118.6, 111.8,
118.1, 111.7, 108.6, 57.3, 56.2, 56.0, 51.9, 46.9, 42.6. FTIR [ꢕ̅
(cm−1)]:
3391, 2939, 1722, 1663, 1597, 1517, 1442, 1327, 1265, 1238, 755. HRMS
[ESI (m/z)] calcd for (C27H25F3N2O4 + Na)+ = 521.16586, found 521.16560
(|Δ| = 1.6 ppm). RF: 0.70 (heptane/AcOEt, 1:2). Yield: 88%.
108.7, 56.9, 56.2, 56.0, 52.5, 46.7, 42.9. FTIR [ꢕ̅
(cm−1)]: 3360, 2961, 2838,
2258, 1725, 1686, 1593, 1517, 1440, 1306, 1263, 1234, 1145, 1027, 842,
751. HRMS [ESI (m/z)] calcd for (C26H24ClF5N2O4S + Na)+ = 613.09632,
found 613.09446 (|Δ| = 3.02 ppm). Yield: 99%.
(2S,6R)-2-(3,4-Dimethoxyphenyl)-4-oxo-6-[4-(pentafluoro-λ6-
sulfanyl)phenyl]-N-phenylpiperidine-1-carboxamide 5cC
According to the general procedure, the reaction of piperidin-4-one 2c
(2S,6R)-N-(2,4-Difluorophenyl)-2-(3,4-dimethoxyphenyl)-6-(4-
fluorophenyl)-4-oxopiperidine-1-carboxamide 5aE
According to the general procedure, the reaction of piperidin-4-one 2a
(2.49 mg, 5.69 µmol) in 1,2-DCE (102.5 mM) with 7C afforded 5cC (3.22
mg, 5.79 µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.81–7.75 (m, 2 H),
7.61–7.55 (m, 2 H), 7.25–7.20 (m, 2 H), 7.06–7.02 (m, 3 H), 6.90–6.86 (m,
2 H), 6.67 (s, 1 H), 6.49–6.47 (m, 1 H), 6.47–6.43 (m, 1 H), 5.16 (dd, J =
11.0, 4.9 Hz, 1 H), 3.89 (s, 3 H), 3.63 (s, 3 H), 3.28 (dd, J = 18.7, 3.7 Hz,
1 H), 3.00 (dd, J = 18.7, 5.9 Hz, 1 H), 2.77 (dd, J = 17.5, 11.0 Hz, 1 H),
2.66 (dd, J = 17.5, 4.9 Hz, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]:
206.3, 156.6, 153.4 (indirect observation), 150.9, 149.7, 146.9, 138.4,
133.8, 129.1, 127.4, 126.9–126.8 (m), 123.9, 120.1, 118.1, 111.7, 108.3,
(2.30 mg, 6.98 µmol) in 1,2-DCE (87.6 mM) with 7E afforded 5aE (3.28
mg, 6.77 µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 8.01 (td, J = 9.1, 5.9
Hz, 1 H), 7.42–7.35 (m, 2 H), 7.12–7.05 (m, 2 H), 6.86–6.77 (m, 3 H), 6.74–
6.67 (m, 2 H), 6.64 (d, J = 1.8 Hz, 1 H), 6.15 (t, J = 5.4 Hz, 1 H), 5.37 (dd,
J = 9.9, 4.9 Hz, 1 H), 3.87 (s, 3 H), 3.72 (s, 3 H), 3.20 (dd, J = 18.5, 5.1 Hz,
1 H), 2.91 (dd, J = 17.7, 9.9 Hz, 1 H), 2.88 (dd, J = 18.5, 5.6 Hz, 1 H), 2.68
(dd, J = 17.7, 4.9 Hz, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 207.0,
162.3 (d, J = 248.0 Hz), 158.2 (dd, J = 245.2, 11.4 Hz), 156.4, 152.6 (dd,
J = 246.0, 12.0 Hz), 150.3, 149.4, 138.1 (d, J = 3.3 Hz), 133.6, 128.6 (d, J
= 8.1 Hz), 123.5 (dd, J = 10.4, 3.8 Hz), 122.7 (dd, J = 9.0, 2.4 Hz), 118.3,
116.3 (d, J = 21.5 Hz), 111.7, 111.1 (dd, J = 21.6, 3.7 Hz), 108.9, 103.4
57.6, 56.2, 55.9, 51.5, 47.0, 42.4. FTIR [ꢕ
1598, 1518, 1265, 1238, 844. HRMS [ESI (m/z)] calcd for (C26H25F5N2O4S
Na)+
579.13474, found 579.13534 (|Δ| 0.1 ppm). RF: 0.22
(heptane/AcOEt, 2:1). Yield: 99%.
̅
(cm−1)]: 3389, 2926, 1725, 1663,
+
=
=
(dd, J = 26.7, 23.3 Hz), 56.5, 56.10, 56.06, 52.6, 46.2, 43.4. FTIR [ꢕ
̅
(2S,6R)-N-(2-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-6-(4-
fluorophenyl)-4-oxopiperidine-1-carboxamide 5aD
(cm−1)]: 3379, 2936, 1721, 1665, 1534, 1511, 1256, 1228, 1025, 962, 849.
HRMS [ESI (m/z)] calcd for (C26H23F3N2O4 + Na)+ = 507.15021, found
507.15113 (|Δ| = 0.7 ppm). RF: 0.29 (heptane/AcOEt, 2:1). Yield: 97%.
According to the general procedure, the reaction of piperidin-4-one 2a (2.4
mg, 7.28 µmol) in 1,2-DCE (90.2 mM) with 7D afforded 5aD (2.58 mg, 5.34
µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 8.09 (dd, J = 8.2, 1.5 Hz, 1 H),
7.44–7.37 (m, 2 H), 7.25–7.17 (m, 2 H), 7.11–7.04 (m, 2 H), 7.02 (s, 1 H),
6.98–6.90 (m, 1 H), 6.85 (dd, J = 8.2, 1.9 Hz, 1 H), 6.82 (d, J = 8.2 Hz, 1
H), 6.73 (d, J = 1.9 Hz, 1 H), 6.15 (t, J = 5.6 Hz, 1 H), 5.50 (dd, J = 9.3, 5.1
Hz, 1 H), 3.86 (s, 3 H), 3.75 (s, 3 H), 3.17 (dd, J = 18.3, 5.6 Hz, 1 H), 2.94
(dd, J = 17.7, 9.3 Hz, 1 H), 2.88 (dd, J = 18.4, 5.6 Hz, 1 H), 2.73 (dd, J =
17.7, 5.1 Hz, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 207.2, 162.3 (d,
J = 247.7 Hz), 156.5, 150.2, 149.3, 138.0 (d, J = 3.2 Hz), 135.8, 133.7,
129.0, 128.6 (d, J = 8.1 Hz), 127.5, 124.0, 123.1, 122.3, 118.5, 116.3 (d, J
(2S,6R)-N-(2,4-Difluorophenyl)-2-(3,4-dimethoxyphenyl)-4-oxo-6-[4-
(trifluoromethyl)phenyl]piperidine-1-carboxamide 5bE
According to the general procedure, the reaction of piperidin-4-one 2b
(1.37 mg, 3.61 µmol) in 1,2-DCE (82.8 mM) with 7E afforded 5bE (1.07 g,
2.00 µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 8.01 (td, J = 9.1, 5.9 Hz,
1 H), 7.70–7.64 (m, 2 H), 7.60–7.55 (m, 2 H), 6.88–6.79 (m, 3 H), 6.73 (s,
1 H), 6.72 (ddd, J = 11.0, 8.3, 2.8 Hz, 1 H), 6.54–6.52 (m, 1 H), 6.35 (t, J
= 5.1 Hz, 1 H), 5.26 (dd, J = 10.5, 4.9 Hz, 1 H), 3.86 (s, 3 H), 3.66 (s, 3 H),
3.27 (dd, J = 18.6, 4.4 Hz, 1 H), 2.95 (dd, J = 18.6, 5.8 Hz, 1 H), 2.82 (dd,
J = 17.6, 10.6 Hz, 1 H), 2.67 (dd, J = 17.6, 4.9 Hz, 1 H). 13C NMR [101
MHz, δ (ppm), CDCl3]: 206.5, 156.4, 158.2 (d, J = 244.4 Hz), 152.3 (dd, J
= 243.9, 11.6 Hz), 150.5, 149.6, 146.5, 133.2, 130.2 (indirect observation),
127.4, 126.2 (q, J = 3.5 Hz), 123.8 (q, J = 270.3 Hz, indirect observation),
123.4 (dd, J = 10.4, 3.9 Hz), 122.8 (dd, J = 8.8, 2.3 Hz), 118.4, 111.8, 111.2
(dd, J = 21.6, 3.8 Hz), 108.5, 103.5 (dd, J = 26.6, 23.3 Hz), 57.2, 56.1, 56.0,
= 21.5 Hz), 111.7, 109.2, 56.2, 56.1, 53.0, 46.2, 43.8. FTIR [ꢕ̅
(cm−1)]: 3365,
2931, 1723, 1666, 1510, 1306, 1264, 1026. HRMS [ESI (m/z)] calcd for
(C26H24ClFN2O4 + Na)+ = 505.13063, found 505.13076 (|Δ| = 0.3 ppm). RF:
0.35 (heptane/AcOEt, 2:1). Yield: 73%.
(2S,6R)-N-(2-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-4-oxo-6-[4-
(trifluoromethyl)phenyl]piperidine-1-carboxamide 5bD
According to the general procedure, the reaction of piperidin-4-one 2b
52.3, 46.7, 42.7. FTIR [ꢕ
1518, 1327, 1257, 1126, 1026. HRMS [ESI (m/z)] calcd for (C27H23F5N2O4
Na)+
557.14702, found 557.14825 (|Δ| 1.2 ppm). RF: 0.31
(heptane/AcOEt, 2:1). Yield: 55%.
̅
(cm−1)]: 3381, 2927, 1723, 1667, 1611, 1535,
(1.98 mg, 5.22 µmol) in 1,2-DCE (82.8 mM) with 7D afforded 5bD (2.15
mg, 4.03 µmol). 1H NMR [500 MHz, δ (ppm), CDCl3]: 8.09 (dd, J = 8.3, 1.5
Hz, 1 H), 7.67–7.63 (m, 2 H), 7.60–7.56 (m, 2 H), 7.25–7.19 (m, 2 H), 7.04
(s, 1 H), 6.95 (ddd, J = 8.1, 7.4, 1.5 Hz, 1 H), 6.86 (dd, J = 8.3, 2.1 Hz, 2
H), 6.82 (d, J = 8.3 Hz, 1 H), 6.65 (d, J = 2.1 Hz, 1 H), 6.31 (t, J = 5.4 Hz,
1 H), 5.43 (dd, J = 9.7, 5.1 Hz, 1 H), 3.85 (s, 3 H), 3.70 (s, 3 H), 3.22 (dd,
J = 18.5, 5.1 Hz, 1 H), 2.94 (dd, J = 18.5, 5.7 Hz, 1 H), 2.87 (dd, J = 17.6,
9.7 Hz, 1 H), 2.74 (dd, J = 17.6, 5.1 Hz, 1 H). 13C NMR [126 MHz, δ (ppm),
CDCl3]: 206.4, 156.4, 150.2, 149.3, 146.3, 135.6, 133.2, 130.2 (q, J = 32.7
Hz), 128.9, 127.4, 127.2, 126.1 (q, J = 3.6 Hz), 124.1, 123.7 (q, J = 272.5
Hz, indirect observation), 123.1, 122.2, 118.5, 111.7, 108.8, 56.6, 56.0,
+
=
=
(2S,6R)-N-(2,4-Difluorophenyl)-2-(3,4-dimethoxyphenyl)-4-oxo-6-[4-
(pentafluoro-λ6-sulfanyl)phenyl]piperidine-1-carboxamide 5cE
According to the general procedure, the reaction of piperidin-4-one 2c
(1.87 mg, 4.27 µmol) in 1,2-DCE (82.9 mM) with 7E afforded 5cE (2.2 mg,
3.7 µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 8.00 (td, J = 9.1, 5.9 Hz, 1
H), 7.83–7.74 (m, 2 H), 7.60–7.52 (m, 2 H), 6.88–6.80 (m, 3 H), 6.79–6.68
(m, 2 H), 6.49 (d, J = 1.2 Hz, 1 H), 6.38 (t, J = 5.0 Hz, 1 H), 5.22 (dd, J =
10.7, 4.9 Hz, 1 H), 3.87 (s, 3 H), 3.65 (s, 3 H), 3.27 (dd, J = 18.6, 4.1 Hz,
1 H), 2.97 (dd, J = 18.6, 5.8 Hz, 1 H), 2.80 (dd, J = 17.6, 10.7 Hz, 1 H),
2.68 (dd, J = 17.6, 4.9 Hz, 1 H). 13C NMR [126 MHz, δ (ppm), CDCl3]:
206.2, 158.3 (dd, J = 245.7, 11.4 Hz), 156.4, 153.5–153.1 (m), 152.7 (dd,
J = 245.7, 11.5 Hz), 150.6, 149.7, 146.5, 133.1, 127.4, 127.0–126.9 (m),
123.4 (dd, J = 10.5, 3.7 Hz), 122.9 (dd, J = 9.0, 2.5 Hz), 118.4, 111.8, 111.2
(dd, J = 21.7, 3.6 Hz), 108.3, 103.5 (dd, J = 26.6, 23.3 Hz), 57.4, 56.2, 55.9,
55.9, 52.8, 46.5, 43.0. FTIR [ꢕ̅
(cm−1)]: 3356, 2961, 1724, 1666, 1593,
1517, 1439, 1327, 1263, 1234, 1124, 754. HRMS [ESI (m/z)] calcd for
(C27H24ClF3N2O4 + Na)+ = 555.12689, found 555.12901 (|Δ| = 2.8 ppm).
RF: 0.33 (heptane/AcOEt, 2:1). Yield: 77%.
(2S,6R)-N-(2-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-4-oxo-6-[4-
(pentafluoro-λ6-sulfanyl)phenyl]piperidine-1-carboxamide 5cD
According to the general procedure, the reaction of piperidin-4-one 2c (3.4
mg, 7.77 µmol) in 1,2-DCE (78.5 mM) with 7D afforded 5cD (4.6 mg, 7.78
µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 8.09–8.05 (m, 1 H), 7.79–7.75
(m, 2 H), 7.58–7.53 (m, 2 H), 7.24–7.20 (m, 2 H), 7.05 (s, 1 H), 6.96 (ddd,
J = 8.2, 7.3, 1.5 Hz, 1 H), 6.87 (dd, J = 8.2, 2.1 Hz, 1 H), 6.83 (d, J = 8.2
Hz, 1 H), 6.60 (d, J = 2.1 Hz, 1 H), 6.32 (t, J = 5.4 Hz, 1 H), 5.40 (dd, J =
51.9, 46.9, 42.5. FTIR [ꢕ
1517, 1257, 843. HRMS [ESI (m/z)] calcd for (C26H23F7N2O4S + H)+
̅
(cm−1)]: 3376, 2962, 1725, 1666, 1610, 1534,
=
593.13395, found 593.13686 (|Δ| = 4.0 ppm). HRMS [ESI (m/z)] calcd for
(C26H23F7N2O4S + Na)+ = 615.11590, found 615.11657 (|Δ| = 0.2 ppm). RF:
0.25 (heptane/AcOEt, 2:1). Yield: 87%.
Synthesis and Full Characterization of Amino Alcohols 11 and 12
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701539
European Journal of Organic Chemistry
FULL PAPER
(2S,4R,6R)-2-(3,4-Dimethoxyphenyl)-6-[4-(pentafluoro-λ6-
sulfanyl)phenyl]piperidin-4-ol 11
Solution A: piperidin-4-one 2c (8.4 mg, 0.019 mmol) dissolved in THF (50.3
mM). Solution B: LiBH4 (2 M solution in THF; 1.5 equiv) dissolved in THF
(75 mM). Solution A (13.33 µL/min) was combined with B (20 µL/min)
inside the glass microreactor (internal volume: 100 µL). The reaction was
performed at 21 °C for 3 min.
FTIR [ꢕ
̅
(cm−1)]: 3404, 2967, 1704, 1627, 1517, 1465, 1263, 1140, 1027,
844, 595. HRMS [ESI (m/z)] calcd for (C23H29F5N2O4S + H)+ = 525.18464,
found 525.18665 (|Δ| = 3.82 ppm). Yield: 84%.
(2S,4R,6R)-N-Benzyl-2-(3,4-dimethoxyphenyl)-4-hydroxy-6-[4-
(pentafluoro-λ6-sulfanyl)phenyl]piperidine-1-carboxamide 6c
According to the general procedure, the reaction of amino alcohol 11 (2.00
mg, 4.55 µmol) in tBuOH (96.5 mM) afforded urea 6c (2.60 mg, 4.54 µmol).
1H NMR [400 MHz, δ (ppm), CDCl3]: 7.76–7.66 (m, 4 H), 7.21–7.12 (m, 3
H), 6.80 (dd, J = 8.2, 2.1 Hz, 1 H), 6.77–6.72 (m, 3 H), 6.54 (d, J = 2.1 Hz,
1 H), 5.44 (t, J = 6.1 Hz, 1 H), 4.80 (t, J = 5.6 Hz, 1 H), 4.47 (dd, J = 11.5,
4.2 Hz, 1 H), 4.27–4.19 (m, 1 H), 4.17 (dd, J = 14.8, 5.8 Hz, 1 H), 4.05 (dd,
J = 14.8, 5.2 Hz, 1 H), 3.85 (s, 3 H), 3.63 (s, 3 H), 2.44 (dt, J = 13.1, 6.3
Hz, 1 H), 2.24 (dt, J = 14.4, 6.5 Hz, 1 H), 2.15 (dt, J = 13.5, 5.1 Hz, 1 H),
1.97 (dt, J = 13.7, 11.1 Hz, 1 H), 1.82 (d, J = 3.3 Hz, 1 H). 13C NMR [101
MHz, δ (ppm), CDCl3]: 160.5, 152.6 (indirect observation), 149.9, 148.9,
148.7, 138.4, 135.6, 128.5, 128.2, 127.3, 127.2, 126.3–126.2, 118.7, 111.5,
1H NMR [500 MHz, δ (ppm), CDCl3]: 7.75–7.69 (m, 2 H), 7.57–7.52 (m, 2
H), 7.00 (d, J = 2.0 Hz, 1 H), 6.96 (dd, J = 8.2, 2.0 Hz, 1 H), 6.83 (d, J =
8.2 Hz, 1 H), 3.99–3.92 (m, 2 H), 3.91 (s, 3 H), 3.87 (s, 3 H), 3.81 (dd, J =
11.3, 2.4 Hz, 1 H), 2.21–2.10 (m, 2 H), 1.62–1.46 (m, 2 H). 13C NMR [126
MHz, δ (ppm), CDCl3]: 153.0 (indirect observation), 149.2, 148.5, 148.2,
136.7, 127.2, 126.3 (quint, J = 4.0 Hz), 118.9, 111.2, 110.1, 69.9, 59.7,
59.4, 56.09, 56.07, 43.9, 43.8. FTIR [ꢕ̅
(cm−1)]: 2936, 2839, 1517, 1262,
1232, 1027, 845, 815. HRMS [ESI (m/z)] calcd for (C19H22F5NO3S + H)+
440.13188, found 440.13125 (|Δ| = 1.44 ppm). Yield: 76%.
=
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-[4-
(trifluoromethyl)phenyl]piperidin-4-ol 12
109.4, 65.6, 59.0, 56.1, 55.9, 55.2, 45.1, 40.9, 37.6. FTIR [ꢕ̅
(cm−1)]: 3410,
N-Selectride (3.95 mL, 3.95 mmol, 1.0 M solution in THF) was added to a
solution of piperidin-4-one 2b (500 mg, 1.32 mmol) in dry THF (96 mL) at
−78 °C. The reaction was stirred for 1 hour and it was quenched with H2O
(100 mL). The solution was allowed to reach 21 °C and then AcOEt was
added. The organic layer was separated and the aqueous layer was
extracted with AcOEt (3 × 50 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered off and
concentrated in vacuo. The residue was purified by SCX-2 column to afford
amino alcohol 12 (456 mg, 1.20 mmol). 1H NMR [400 MHz, δ (ppm),
CDCl3]: 7.66–7.53 (m, 4 H), 7.04–6.97 (m, 2 H), 6.84 (d, J = 8.1 Hz, 1 H),
4.40–4.32 (m, 2 H), 4.25 (dd, J = 11.7, 2.7 Hz, 1 H), 3.91 (s, 3 H), 3.87 (s,
3 H), 1.95–1.87 (m, 2 H), 1.86–1.70 (m, 2 H). 13C NMR [101 MHz, δ (ppm),
CDCl3]: 149.4, 149.1, 148.4, 137.5 (indirect observation), 129.4 (indirect
observation), 127.3, 125.5 (q, J = 3.7 Hz), 123.0 (indirect observation),
2936, 1690, 1560, 1541, 1263, 1139, 1027, 842, 750, 595. HRMS [ESI
(m/z)] calcd for (C27H29F5N2O4S + Na)+ = 595.16659, found 595.16478 (|Δ|
= 3.04 ppm). Yield: 99%.
Synthesis and Full Characterization of Aryl Ureas 6d and 6e
Solution A: compound 11 (1.0 equiv) dissolved in 1,2-DCE (95.6–105.0
mM). Solution B: aryl isocyanate (7C–E, 1.1 equiv) dissolved in 1,2-DCE
(0.1 M). Solution A (2.80 µL/min) was combined with B (3.08 µL/min) inside
the glass microreactor (internal volume: 100 µL). The reaction was
performed at 80 °C for 17 min.
(2S,4R,6R)-2-(3,4-Dimethoxyphenyl)-4-hydroxy-6-[4-(pentafluoro-λ6-
sulfanyl)phenyl]-N-phenylpiperidine-1-carboxamide 6d
According to the general procedure, the reaction of amino alcohol 11 (2.57
mg, 5.85 µmol) in 1,2-DCE (95.6 mM) afforded urea 6d (3.26 mg, 5.84
µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.80–7.76 (m, 2 H), 7.75–7.70
(m, 2 H), 7.20–7.14 (m, 2 H), 6.99–6.90 (m, 4 H), 6.87 (d, J = 8.2 Hz, 1 H),
6.56 (s, 1 H), 6.51 (d, J = 2.1 Hz, 1 H), 5.80 (t, J = 5.8 Hz, 1 H), 4.61 (dd,
J = 12.0, 4.3 Hz, 1 H), 4.36–4.24 (m, 1 H), 3.88 (s, 3 H), 3.62 (s, 3 H), 2.58
(dt, J = 14.3, 6.9 Hz, 1 H), 2.37 (dt, J = 14.9, 5.4 Hz, 1 H), 2.18 (dt, J =
13.6, 5.1 Hz, 1 H), 2.03 (dt, J = 13.7, 11.6 Hz, 1 H), 1.89–1.85 (m, 1 H).
13C NMR [101 MHz, δ (ppm), CDCl3]: 157.6, 152.6 (indirect observation),
150.4, 149.3, 148.9, 138.5, 135.3, 129.0, 128.2, 126.4–126.2 (m), 123.6,
119.8, 118.5, 111.6, 109.1, 65.1, 59.1, 56.2, 55.9, 53.8, 41.0, 36.6. FTIR
118.9, 111.3, 110.2, 66.2, 56.09, 56.07, 56.0, 55.7, 41.66, 41.65. FTIR [ꢕ
̅
(cm−1)]: 2936, 1517, 1465, 1326, 1263, 1163, 1123, 1067, 1027, 806.
HRMS [ESI (m/z)] calcd for (C20H22F3NO3 + H)+ = 382.16300, found
382.16336 (|Δ| = 0.94 ppm). Yield: 91%.
Synthesis and Full Characterization of Alkyl Ureas 6a–c
Solution A: compound 11 (1.0 equiv) dissolved in tBuOH (94.3–96.5 mM).
Solution B: alkyl isocyanate (7A, 7B or 7F, 1.5 equiv) dissolved in tBuOH
(0.1 M). Solution A (2.35 µL/min) was combined with B (3.53 µL/min) inside
the glass microreactor (internal volume: 100 µL). The reaction was
performed at 50 °C for 17 min.
[ꢕ̅
(cm−1)]: 3388, 2933, 2841, 1686, 1647, 1501, 1443, 1420, 1264, 1237,
1140, 1027, 843, 754. HRMS [ESI (m/z)] calcd for (C26H27F5N2O4S + Na)+
= 581.15094, found 581.14995 (|Δ| = 1.70 ppm). Yield: 99%.
(2S,4R,6R)-2-(3,4-Dimethoxyphenyl)-N-ethyl-4-hydroxy-6-[4-
(2S,4R,6R)-N-(2-Chlorophenyl)-2-(3,4-dimethoxyphenyl)-4-hydroxy-
6-[4-(pentafluoro-λ6-sulfanyl)phenyl]piperidine-1-carboxamide 6e
According to the general procedure, the reaction of amino alcohol 11 (3.40
mg, 7.74 µmol) in 1,2-DCE (105.0 mM) afforded urea 6e (3.81 mg, 6.42
µmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 8.01 (dd, J = 8.6, 1.6 Hz, 1 H),
7.79–7.75 (m, 2 H), 7.75–7.70 (m, 2 H), 7.21–7.14 (m, 2 H), 6.97 (s, 1 H),
6.95–6.87 (m, 2 H), 6.82 (d, J = 8.3 Hz, 1 H), 6.61 (d, J = 2.2 Hz, 1 H), 5.83
(t, J = 6.0 Hz, 1 H), 4.85 (dd, J = 11.1, 4.8 Hz, 1 H), 4.39–4.37 (m, 1 H),
3.84 (s, 3 H), 3.65 (s, 3 H), 2.57 (dt, J = 14.4, 7.0 Hz, 1 H), 2.36 (dt, J =
14.9, 5.8 Hz, 1 H), 2.26 (dt, J = 13.9, 5.4 Hz, 1 H), 2.09 (dt, J = 13.9, 10.5
Hz, 1 H), 1.87 (d, J = 3.6 Hz, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]:
157.1, 152.6 (indirect observation), 150.1, 149.1, 148.5, 135.8, 134.8,
129.0, 128.2, 127.5, 126.5–126.3 (m), 123.9, 123.0, 122.0, 119.0, 111.8,
(pentafluoro-λ6-sulfanyl)phenyl]piperidine-1-carboxamide 6a
According to the general procedure, the reaction of amino alcohol 11 (2.37
mg, 5.39 µmol) in tBuOH (94.6 mM) afforded urea 6a (2.33 mg, 4.56 µmol).
1H NMR [400 MHz, δ (ppm), CDCl3]: 7.74–7.70 (m, 2 H), 7.70–7.65 (m, 2
H), 6.85 (dd, J = 8.3, 2.0 Hz, 1 H), 6.81 (d, J = 8.3 Hz, 1 H), 6.57 (d, J =
2.0 Hz, 1 H), 5.39 (t, J = 6.2 Hz, 1 H), 4.43 (t, J = 5.8 Hz, 1 H), 4.40 (dd, J
= 11.7, 4.3 Hz, 1 H), 4.27–4.14 (m, 1 H), 3.86 (s, 3 H), 3.69 (s, 3 H), 2.93
(qd, J = 7.3, 5.4 Hz, 2 H), 2.43 (dt, J = 13.3, 6.2 Hz, 1 H), 2.24–2.10 (m, 2
H), 1.94 (dt, J = 13.5, 11.2 Hz, 1 H), 1.78 (d, J = 3.7 Hz, 1 H). 13C NMR
[101 MHz, δ (ppm), CDCl3]: 160.7, 152.7 (indirect observation), 149.9,
148.9, 148.7 (indirect observation), 135.7, 128.1, 126.3–126.1 (m), 118.7,
111.4, 109.5, 65.8, 59.2, 56.1, 56.0, 55.3, 41.2, 37.8, 35.7, 14.8. FTIR [ꢕ
̅
(cm−1)]: 3414, 2937, 1627, 1517, 1263, 1140, 1027, 846, 594. HRMS [ESI
(m/z)] calcd for (C22H27F5N2O4S + Na)+ = 533.15094, found 533.15027 (|Δ|
= 1.26 ppm). Yield: 85%.
109.2, 64.9, 58.3, 56.2, 56.0, 54.0, 40.8, 36.6. FTIR [ꢕ
2838, 2258, 1735, 1663, 1517, 1439, 1263, 1140, 1027, 843, 754. HRMS
̅
(cm−1)]: 3362, 2936,
[ESI (m/z)] calcd for (C26H26ClF5N2O4S
+ = 593.13002, found
H)+
593.12885 (|Δ| = 1.98 ppm). Yield: 83%.
(2S,4R,6R)-2-(3,4-Dimethoxyphenyl)-4-hydroxy-N-isopropyl-6-[4-
(pentafluoro-λ6-sulfanyl)phenyl]piperidine-1-carboxamide 6b
Synthesis and Full Characterization of Ureas 13a and 13b
According to the general procedure, the reaction of amino alcohol 11 (2.80
mg, 6.37 µmol) in tBuOH (94.3 mM) afforded urea 6b (2.76 mg, 5.34 µmol).
1H NMR [400 MHz, δ (ppm), CDCl3]: 7.73–7.68 (m, 2 H), 7.68–7.63 (m, 2
H), 6.86 (dd, J = 8.3, 2.0 Hz, 1 H), 6.81 (d, J = 8.2 Hz, 1 H), 6.62 (d, J =
2.1 Hz, 1 H), 5.19 (dd, J = 7.4, 5.1 Hz, 1 H), 4.36–4.28 (m, 2 H), 4.24–4.12
(m, 1 H), 3.86 (s, 3 H), 3.72 (s, 3 H), 3.60–3.50 (m, 1 H), 2.46–2.35 (m, 1
H), 2.21–2.08 (m, 2 H), 1.99–1.87 (m, 1 H), 0.75 (d, J = 6.5 Hz, 3 H), 0.61
(d, J = 6.5 Hz, 3 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 160.3, 152.7
(indirect observation), 149.8, 148.9, 148.4, 135.5, 128.2, 126.2–126.0 (m),
119.0, 111.4, 109.9, 66.2, 59.7, 56.2, 56.0, 42.4, 41.4, 38.4, 22.8, 22.5.
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-4-hydroxy-N-isopropyl-6-[4-
(trifluoromethyl)phenyl]piperidine-1-carboxamide 13a and 13b
Isopropyl isocyanate (7B; 0.01 mL, 0.12 mmol) was added to a solution of
piperidin-4-ol 12 (46.2 mg, 0.12 mmol) in CH2Cl2 (1.2 mL) at 21 °C and the
reaction was stirred for 20 hours. The solvent was removed under vacuo
and the crude was purified by column chromatography
(CH2Cl2→CH2Cl2/MeOH, 10:1) to afford compounds 13a and 13b (21.5
mg, 0.046 mmol). Combined yield: 38%.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701539
European Journal of Organic Chemistry
FULL PAPER
13a: 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.59–7.49 (m, 4 H), 6.84–6.74
(m, 2 H), 6.64 (bs, 1 H), 5.65 (t, J = 5.4 Hz, 1 H), 4.90 (dd, J = 10.0, 4.1
Hz, 1 H), 4.43 (quint, J = 5.2 Hz, 1 H), 4.33 (d, J = 7.4 Hz, 1 H), 3.83 (s, 3
H), 3.82–3.71 (m, 1 H), 3.71 (s, 3 H), 2.76–2.64 (m, 1 H), 2.15–2.07 (m, 1
H), 2.00 (dt, J = 15.0, 5.4 Hz, 1 H), 1.84 (dt, J = 14.9, 3.8 Hz, 1 H), 0.89 (d,
J = 6.5 Hz, 3 H), 0.74 (d, J = 6.4 Hz, 3 H). 13C NMR [101 MHz, δ (ppm),
CDCl3]: 159.3, 149.7, 148.65–148.59 (m), 148.5, 136.1, 129.2 (q, J = 32.6
Hz), 127.4, 125.5 (q, J = 3.7 Hz), 122.8 (indirect observation), 118.3, 111.3,
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Comb. Sci. 2013, 15, 235-239; b) P. P. Lange, K. James, ACS Comb.
Sci. 2012, 14, 570-578; c) M. Baumann, I. R. Baxendale, C. Kuratli, S. V.
Ley, R. E. Martin, J. Schneider, ACS Comb. Sci. 2011, 13, 405-413.
Reactions were carried out using the FlowStart Evo equipment and
microreactors purchased from FutureChemistry (futurechemistry.com
accessed Sep 11, 2017).
[6]
[7]
109.6, 62.4, 56.0, 55.9, 54.1, 52.1, 42.8, 39.6, 36.1, 23.2, 22.9. FTIR [ꢕ
̅
(cm−1)]: 3415, 2965, 2937, 1619, 1517, 1465, 1327, 1262, 1164, 1123,
[8]
[9]
1070, 1019, 808. HRMS [ESI (m/z)] calcd for (C24H29F3N2O4 + Na)+
=
489.19771, found 489.19701 (|Δ| = 1.43 ppm).
13b: 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.69–7.62 (m, 2 H), 7.61–7.54
(m, 2 H), 6.90–6.84 (m, 1 H), 6.81 (dd, J = 8.2, 0.8 Hz, 1 H), 6.67 (d, J =
1.9 Hz, 1 H), 5.12 (dd, J = 7.3, 5.2 Hz, 1 H), 4.36 (dd, J = 11.7, 3.9 Hz, 1
H), 4.32 (d, J = 7.5 Hz, 1 H), 4.23–4.11 (m, 1 H), 3.86 (s, 3 H), 3.73 (s, 3
H), 3.60–347 (m, 1 H), 2.41–2.33 (m, 1 H), 2.20–2.10 (m, 2 H), 2.01–1.91
(m, 1 H), 0.72 (d, J = 5.9 Hz, 3 H), 0.61 (d, J = 6.6 Hz, 3 H). 13C NMR [101
MHz, δ (ppm), CDCl3]: 160.4, 149.7, 148.8, 148.4, 135.6, 129.4 (indirect
observation), 128.2, 125.4, 122.9 (indirect observation), 119.1, 111.3,
[10] 1,3-Diethylurea was obtained as a side product in the reaction mixture
(ratio 5cA/1,3-diethylurea 1:0.28).
[11] The presence of 1,3-diethylurea present was reduced (ratio 5cA/1,3-
diethylurea 1:0.1).
110.0, 66.3, 59.6, 56.7, 56.1, 56.0, 42.4, 41.2, 38.7, 22.8, 22.5. FTIR [ꢕ
̅
[12] At very low flow rates, stabilization and pressure of the equipment may
take long; therefore, a stabilization time is calculated and run before the
collecting product fraction. The stabilization time is calculated following
equation 1:
(cm−1)]: 3414, 2930, 1620, 1517, 1465, 1325, 1263, 1164, 1122, 1027, 842.
HRMS [ESI (m/z)] calcd for (C24H29F3N2O4 + Na)+ = 489.19771, found
489.19688 (|Δ| = 1.70 ppm).
⁄
ꢀꢁꢂꢃꢄꢅꢄꢆꢂꢁꢄꢇꢈ ꢉꢄꢊꢋ ꢌ 3 ꢍ ꢎꢋꢂꢏꢁꢇꢐ ꢑꢇꢅꢒꢊꢋ ꢉꢇꢁꢂꢅ ꢓꢅꢇꢔ ꢎꢂꢁꢋ (Eq 1)
[13] a) M. Hutchby in Novel Synthetic Chemistry of Ureas and Amides,
Springer, Berlin Heidelberg, 2013, pp. 57-70; b) M. Hutchby, C. E.
Houlden, J. G. Ford, S. N. G. Tyler, M. R. Gagn, G. C. Lloyd-Jones, K. I.
Booker-Milburn. Angew. Chem. Int. Ed. 2009, 48, 8721–8724.
[14] S. R. Neufeldt, G. Jimenez-Oses, D. L. Comins, K. N. Houk, J. Org.
Chem. 2014, 79, 11609-11618.
Acknowledgements
This work has been supported by the FP7 Marie Curie Actions of
the European Commission via the ITN ECHONET Network
(MCITN-2012-316379).
[15] The reduction of ketone 2 to alcohol 12 was unsuccessfully performed in
flow.
[16] 1,3-Dibenzylurea was present in the reaction mixture (ratio 6c/1,3-
dibenzylurea 1:0.15).
Keywords: continuous flow • nitrogen heterocycles • urea
[17] L. Y. Vargas Méndez, V. V. Kouznetsov, Cent. Eur. J. Chem. 2011, 9,
877-885.
functionality • atropisomers • piperidin-4-one
[18] We do not rule out the possibility of a mixture of rotamers because the
13C NMR chemical shift of the carbamoyl carbon is δ 159.3 ppm and the
IR stretching frequency of the C=O is at 1619 cm−1 in the IR (higher
values would be expected if atropisomers were observed, although the
absence of examples of this phenomenon in the literature makes the
prediction of those values difficult).
[1]
[2]
I. Gallou, Org. Prep. Proced. Int. 2007, 39, 355-383.
A. D. Jagtap, N. B. Kondekar, A. A. Sadani, J. W. Chern, Curr. Med.
Chem. 2017, 24, 622-651.
[3]
[4]
E. Kühle, E. Klauke, Angew. Chem. Int. Ed. 1977, 16, 735-806.
G. Theodoridis in Fluorine and the Environment, Vol. 2 (Ed.: A. Tressaud),
Elsevier, Oxford, 2006, pp. 121-175.
[19] Compounds 13a and 13b were isolated after column chromatography of
the reaction in batch of amino alcohol 12 and isopropyl isocyanate 7B.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701539
European Journal of Organic Chemistry
FULL PAPER
Layout 2:
FULL PAPER
Key Topic* Library synthesis in flow
Alejandra Riesco-Domínguez, Daniel
Blanco-Ania and Floris P. J. T. Rutjes*
Page No. – Page No.
Title: Continuous Flow Synthesis of
Urea-Containing Compound Libraries
Based on the Piperidin-4-one
Scaffold.
Two libraries of ureas based on the piperidin-4-one scaffold have been developed in continuous flow and twenty drug-like
compounds were synthesized in moderate to high yields.
This article is protected by copyright. All rights reserved.